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Transcriptomic Analysis of Pluripotent Stem Cells: Insights Into Health and Disease Jia-Chi Yeo1,2 and Huck-Hui Ng1,2,3,4,5,*

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Transcriptomic Analysis of Pluripotent Stem Cells: Insights Into Health and Disease Jia-Chi Yeo1,2 and Huck-Hui Ng1,2,3,4,5,* Yeo and Ng Genome Medicine 2011, 3:68 http://genomemedicine.com/content/3/10/68 REVIEW Transcriptomic analysis of pluripotent stem cells: insights into health and disease Jia-Chi Yeo1,2 and Huck-Hui Ng1,2,3,4,5,* Abstract types, termed ‘pluripotency’, allows researchers to study early mammalian development in an artificial setting and Embryonic stem cells (ESCs) and induced pluripotent offers opportunities for regenerative medicine, whereby stem cells (iPSCs) hold tremendous clinical potential ESCs could generate clinically relevant cell types for because of their ability to self-renew, and to tissue repair. However, this same malleability of ESCs dierentiate into all cell types of the body. This unique also renders it a challenge to obtain in vitro differentiation capacity of ESCs and iPSCs to form all cell lineages of ESCs to specific cell types at high efficacy. erefore, is termed pluripotency. While ESCs and iPSCs are harnessing the full potential of ESCs requires an in-depth pluripotent and remarkably similar in appearance, understanding of the factors and mechanisms regulating whether iPSCs truly resemble ESCs at the molecular ESC pluripotency and cell lineage decisions. level is still being debated. Further research is therefore Early studies on ESCs led to the discovery of the core needed to resolve this issue before iPSCs may be safely pluripotency factors Oct4, Sox2 and Nanog [1], and, applied in humans for cell therapy or regenerative increasingly, the use of genome-level screening assays has medicine. Nevertheless, the use of iPSCs as an in vitro revealed new insights by uncovering additional trans- human genetic disease model has been useful in cription factors, transcriptional cofactors and chromatin studying the molecular pathology of complex genetic remodeling complexes involved in the maintenance of diseases, as well as facilitating genetic or drug screens. pluripotency [1]. e study of ESC transcriptional regu- Here, we review recent progress in transcriptomic lation is also useful in the understanding of human approaches in the study of ESCs and iPSCs, and discuss diseases. ESCs, for instance, are known to share certain how deregulation of these pathways may be involved cellular and molecular signatures similar to those of in the development of disease. Finally, we address the cancer cells [2], and deregulation of ESC-associated importance of these advances for developing new trans criptional regulators has been implicated in many therapeutics, and the future challenges facing the human developmental diseases. clinical application of ESCs and iPSCs. Despite the promising potential, the use of human Keywords Embryonic stem cells, gene expression, ESCs (hESCs) in clinical applications has been slow induced pluripotent stem cells, pluripotency, because of ethical, immunological and tumorigenicity regenerative medicine, therapy, transcriptional concerns [3]. ese ethical and immunogenicity issues regulation, transcriptomics. were seemingly overcome by the creation of induced pluripotent stem cells (iPSCs), whereby exogenous expres sion of Oct4, Sox2, Klf4 and c-Myc in differentiated cells could revert them to pluripotency [4]. However, the Stem cell transcriptomics and transcriptional question of whether these iPSCs truly resemble ESCs is networks still actively debated and remains unresolved [5]. Never- Embryonic stem cells (ESCs) have the unique ability to theless, the application of iPSCs as an in vitro human self-renew and differentiate into cells of all three germ genetic disease model has been successful in revealing layers of the body. is capacity to form all adult cell novel molecular disease pathologies, as well as facilitating genetic or drug screenings [6]. In this review, we describe recent advances in under- *Correspondence: [email protected] 1Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, standing the ESC and iPSC transcriptional network, and Genome, Singapore 138672 also discuss how deregulation of ESC pathways is Full list of author information is available at the end of the article implicated in human diseases. Finally, we address how the knowledge gained through transcriptional studies of © 2010 BioMed Central Ltd © 2011 BioMed Central Ltd ESCs and iPSCs has impacted translational medicine. Yeo and Ng Genome Medicine 2011, 3:68 Page 2 of 12 http://genomemedicine.com/content/3/10/68 Transcriptomic approaches for studying stem cells Table 1. Transcriptomic approaches for studying stem cells The transcriptome is the universe of expressed transcripts Objective Method Reference within a cell at a particular state [7]; and understanding DNA sequencing NGS [65] the ESC transcriptome is key towards appreciating the mRNA expression analysis Microarray [58] mechanism behind the genetic regulation of pluripotency RNA-seq [93] and differentiation. The methods used to study gene expression patterns can be classified into two groups: (1) miRNA expression analysis Microarray [11] those using hybridization-based approaches, and (2) RNA-seq [18] those using sequencing-based approaches (Table 1). lncRNA expression analysis Microarray [12,13] For hybridization-based methods, the commonly used Identification of alternative splicing isoforms Microarray [22,94] ‘DNA microarray’ technique relies on hybridization RNA-seq [95] between expressed transcripts and microarray printed Mapping of protein-DNA binding ChIP-chip [9,10,24] oligo nucleotide (oligo) probes from annotated gene regions [7]. In addition to allowing the identification of ChIP-PET [23] highly expressed genes, microarrays also enable the study ChIP-seq [15] of gene expression changes under various conditions. DNA methylation profiling BS-seq [68] However, microarrays have their limitations, whereby MethylC-seq [68] prior knowledge of genomic sequences is required, and DIP-seq [16] cross-hybridization of oligo probes may lead to false Mapping of long-range chromatin interactions ChIA-PET [17] identification [7]. Subsequently, later versions of micro- arrays were modified to include exon-spanning probes 3C [29] for alternative-spliced isoforms, as well as ‘tiling arrays’, Identification of RNA-protein interactions RIP-seq [19] which comprise oligo probes spanning large genomic RIP and regions to allow for the accurate mapping of gene trans- direct RNA [14] quantification cripts [7,8]. Indeed, conventional microarrays and tiling arrays have been instrumental in advancing our under- BS-seq, bisulfite sequencing; ChIA-PET, chromatin interaction analysis with paired-end tag sequencing; ChIP-chip, chromatin immunoprecipitation standing of ESC transcriptional regulation (Table 1) on chip; ChIP-PET, chromatin immunoprecipitation with paired-end tag through the mapping of ESC-associated transcription- sequencing; ChIP-seq, chromatin immunoprecipitation and sequencing; DIP- seq, DNA immunoprecipitation and sequencing; MethylC-seq, methylcytosine factor binding sites (chromatin immunoprecipitation sequencing; NGS, next-generation sequencing; RIP, RNA-binding protein (ChIP)-chip) [9,10], identification of microRNA (miRNA) immunoprecipitation; RIP-seq, RNA-binding protein immunoprecipitation and regulation in ESCs [11], as well as the identification of sequencing; RNA-seq, RNA sequencing; 3C, chromosome conformation capture. long non-coding RNA (lncRNA) [12] and long intergenic non-coding RNA (lincRNA) [13,14]. Transcriptomics has been instrumental in the study of Sequence-based transcriptomic analysis on the other alternative splicing events. It has been suggested that hand involves direct sequencing of the cDNA. Initially, around 95% of all multi-exon human genes undergo Sanger sequencing techniques were used to sequence alternative splicing to generate different protein variants gene transcripts, but these methods were considered for an assortment of cellular processes [20], and that expensive and low throughput [7]. However, with the alter native splicing contributes to higher eukaryotic development of next-generation sequencing (NGS), such complexity [21]. In mouse ESCs (mESCs) undergoing as the 454, Illumina and SOLiD platforms, it is now embryoid body formation, exon-spanning microarrays possible to perform affordable and rapid sequencing of have identified possible alternative splicing events in massive genomic information [8]. Importantly, NGS when genes associated with pluripotency, lineage specification coupled with transcriptome sequencing (RNA-seq) offers and cell-cycle regulation [22]. More interestingly, it was high-resolution mapping and high-throughput transcrip- found that alternative splicing of the Serca2b gene during tome data, revealing new insights into transcriptional ESC differentiation resulted in a shorter Serca2a isoform events such as alternative splicing, cancer fusion-genes with missing miR-200 targeting sites in its 3’-UTR. Given and non-coding RNAs (ncRNAs). This versatility of NGS that miR-200 is highly expressed in cardiac lineages, and for ESC research is evident through its various appli ca- that Serca2a protein is essential for cardiac function, the tions (Table 1), such as chromatin immunoprecipitation results suggest that during mESC differentiation some coupled to sequencing (ChIP-seq) [15], methylated DNA genes may utilize alternative splicing to bypass lineage- immunoprecipitation coupled to sequencing (DIP-seq) specific miRNA silencing [22]. With the largely [16], identification of long-range chromatin interactions [17], uncharacterized nature of alternative splicing in ESCs, miRNA profiling
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